Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5](=O)[CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(O)=O.[CH2:17]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:25]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:5]1[CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:1])[CH2:6]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH2:25]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:5]1[CH2:4][C@H:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@H:2]([CH3:1])[CH2:6]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CCOC(=O)C1CC(=O)CC1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)CC1C
Product: CCOC(=O)[C@H]1C[C@@H](N(Cc2ccccc2)Cc2ccccc2)C[C@H]1C
Temperature: 0 °C
Reaction time: 20 h
Yield: 150 %

Procedure:
A round bottom flask was charged with ethyl 2-methyl-4-oxocyclopentanecarboxylate (10.0 g, 58.8 mmol) and DCE (180 mL). The solution was cooled to about 0° C. and AcOH (5.7 mL, 100 mmol) and dibenzylamine (11.3 mL, 58.8 mmol) were added dropwise, resulting in formation of a thick suspension. The reaction mixture was warmed to about 10° C. and sodium triacetoxyborohydride (21.2 g, 100 mmol) was added portionwise. The reaction mixture was stirred at ambient temperature for about 20 h then slowly poured into stirred saturated aqueous NaHCO3 (300 mL) and stirred for about 20 min. The layers were separated and the aqueous phase was extracted with DCM (3×100 mL). The combined organic extracts were washed with brine (2×100 mL), dried over anhydrous Na2SO4, and concd under reduced pressure. The crude yellow oil was purified via silica gel chromatography eluting with a gradient of 0-30% EtOAc in heptane to give ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate (scalemic mixture of diastereomers), predominantly (1S,2R,4S) ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate (15.5 g, 75%) as a colorless oil: 1H NMR (pyridine-d5) δ 7.53 (dd, J=0.9, 7.9 Hz, 4H), 7.43-7.35 (m, 4H), 7.33-7.25 (m, 2H), 4.22-4.06 (m, 2H), 3.79 (d, J=14.2 Hz, 2H), 3.70 (d, J=14.2 Hz, 2H), 3.34-3.22 (m, 1H), 2.76 (dd, J=7.9, 16.6 Hz, 1H), 2.25-2.13 (m, 1H), 2.09-1.94 (m, 2H), 1.88-1.79 (m, 1H), 1.52 (dd, J=10.5, 22.5 Hz, 1H), 1.16 (t, J=7.1 Hz, 3H), 0.98 (d, J=7.0 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-])=O.C(OCC)(=O)C>CO.[Pt](=O)=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:15]=[CH:14]3)=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(cnn3-c3cccnc3)c2)nc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(Oc2ccc3c(cnn3-c3cccnc3)c2)nc1
Reaction time: 3 h
Yield: 104.3 %

Procedure:
To a solution of 5-(5-Nitro-pyridin-2-yloxy)-1-pyridin-3-yl-1H-indazole (0.79 mmol) in 10 mL of methanol was added 10 mL of ethyl acetate and 30 mg of platinum (IV) oxide. After shaking under 50 psi of H2 for 3 h, the mixture was filtered through a pad of Celite and concentrated in vacuo, affording 0.25 g of 5-(5-Amino-pyridin-2-yloxy)-1-pyridin-3-yl-1H-indazole
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[Cl:16][C:17]1[CH:18]=[N+:19]([O-:37])[CH:20]=[C:21]([Cl:36])[C:22]=1[CH2:23][C@@H:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1)O.CCN=C=NCCCN(C)C.Cl.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][C@H:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[CH2:23][C:22]2[C:21]([Cl:36])=[CH:20][N+:19]([O-:37])=[CH:18][C:17]=2[Cl:16])=[O:12])=[CH:9][CH:8]=1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Reactant: O=C(O)c1ccc(CC2OCCO2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CC3OCCO3)cc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.9 %

Procedure:
To a solution of 4-((1,3-dioxolan-2-yl)methyl)benzoic acid (362 mg, 1.05 mmol) in DCM (9 mL) was added (1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (200 mg, 0.96 mmol) followed by DMAP (58 mg, 0.48 mmol) and EDC.HCl (396 mg, 1.9 mmol). The mixture was allowed to stir a room temperature for 18 hours and then water (20 mL) and DCM (20 mL) were added and the organic phase was passed through a hydrophobic frit. The solvent was removed in vacuo and the crude material was purified by silica gel column chromatography, eluting with 30-100% EtOAc in DCM, to afford the title compound as an off-white solid (497 mg, 97%).
Reaction SMILES: [NH2:1][C:2]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3]1.S(Cl)([Cl:10])=O.[CH2:12](O)[CH3:13]>>[ClH:10].[NH2:1][C:2]1([C:5]([O:7][CH2:12][CH3:13])=[O:6])[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CCO
Reactant: NC1(C(=O)O)CC1
Product: CCOC(=O)C1(N)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A suspension of 1-aminocyclopropanecarboxylic acid (5.8 g, 57.4 mmol) in 300 mL of ethanol was cooled to 0° C., thionyl chloride (20.5 g, 172.7 mmol) was added drop-wise over 30 minutes. Then the cold bath was removed and the reaction mixture was heated at reflux for 2 hours, then the mixture was stirred at room temperature for 16 hours. The solvent was evaporated at 40° C. under reduced pressure to give ethyl 1-aminocyclopropanecarboxylate hydrochloride (9.53 g, 100%) as a solid. It was used directly in the next step without further purification. MS: (M+H)+=130.2; 1H NMR (300 MHz, DMSO): δ 9.04 (brs, 3H), 4.14 (q, 2H, J=6.9 Hz), 1.45 (d, 2H, J=3.3 Hz), 1.37 (d, 2H, J=3.2 Hz), 1.19 (t, 3H, J=6.9 Hz).
Reaction SMILES: C[O:2][P:3]([CH:7]([OH:24])[CH2:8][CH2:9]/[CH:10]=[C:11](\[CH3:23])/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])(=[O:6])[O:4]C.N1C(C)=CC(C)=CC=1C.C[Si](Br)(C)C>ClCCl.C1(C)C=CC=CC=1>[OH:24][CH:7]([P:3](=[O:2])([OH:6])[OH:4])[CH2:8][CH2:9]/[CH:10]=[C:11](\[CH3:23])/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:20])[CH3:21]
Reactant: COP(=O)(OC)C(O)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Agent: C[Si](C)(C)Br
Solvent: Cc1cc(C)nc(C)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC(O)P(=O)(O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of dimethyl[1-hydroxy-(E,E)-5,9,13-trimethyl-4,8,12-tetradecatrienyl]phosphonate (98 mg, 0.253 mmol) and 2,4,6-collidine (0.134 ml, 1.014 mmol) in dichloromethane (3 ml) under arson at 0° C., was added trimethylsilyl bromide (0.134 ml, 1.013 mmol) and the resulting mixture stirred at 0° C. for 30 min. and then at r.t. for 5 hr. The resulting white suspension was diluted with toluene (10 ml) and the solvent evaporated in vacuo, the resulting white solid was dissolved in ethylacetate and water and the pH was adjusted to 3 by the addition of 1M HCl solution. The organic layer was separated, dried (Na2SO4) and evaporated to afford a glassy residue. The solid was washed with acetonitrile (2×5 ml) and the white solid filtered off and dried in vacuo to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH2:13][CH2:12][CH:11]([S:14]([CH2:17][CH:18]2[CH2:20][CH2:19]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:5].[CH3:33][S-:34].[Na+].O>CC(O)C>[CH:18]1([CH2:17][S:14]([CH:11]2[CH2:12][CH2:13][C:8]([CH2:7][NH:6][C:4](=[O:5])[C:3]3[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[N:28][C:2]=3[S:34][CH3:33])([CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH2:9][CH2:10]2)(=[O:16])=[O:15])[CH2:20][CH2:19]1
Reactant: C[S-]
Reactant: O=C(NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1)c1ccc(C(F)(F)F)nc1Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CSc1nc(C(F)(F)F)ccc1C(=O)NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Yield: 97.8 %

Procedure:
A solution of 2-chloro-N-(4-cyclopropylmethanesulfonyl-1-cyclopropylmethylcyclohexylmethyl)-6-trifluoromethylnicotinamide (75 mg, 0.15 mmol) in propan-2-ol (5 ml) was treated with sodium thiomethoxide (21 mg, 0.30 mmol) and the mixture was heated under reflux for 4 hours. Water (1 ml) was added and the solvent was evaporated. The residue was partitioned between dichloromethane (5 ml) and water (5 ml) and the layers were separated using a 5 micron PTFE frit and the filtrate was evaporated. The residue was purified by preparative plate chromatography eluting with 10% ethyl acetate in dichloromethane. Collecting the appropriate band followed by trituration of the silica with ethyl acetate, filtration and evaporation gave a pale yellow foam (74 mg, 97%). 1H NMR δ (ppm) (CDCl3): 8.00 (1H, d, J=7.8 Hz), 7.41 (1H, d, J=7.8 Hz), 6.40 (1H, s), 3.64 (2H, d, J=6.3 Hz), 2.98-2.89 (3H, m), 2.63 (3H, s), 2.09-1.90 (6H, m), 1.46-1.16 (5H, m), 0.79-0.69 (3H, m), 0.55-0.51 (2H, m), 0.45-0.40 (2H, m), 0.09-0.06 (2H, m). MS (m/e)=505.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[I:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[C:13]([O-])([O-])=O.[K+].[K+].CI>O>[CH3:13][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[I:11])[C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(O)c(I)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1cc2c(cc1I)C(=O)CC2

Procedure:
The product of Example 60 was added to methyl ethyl ketcne (50 ml), K2CO3 (5 g) and methyl iodide (5 ml) then heated at reflux for 4 1/2 hrs. The reaction was cooled, H2O added, followed by an EtOAc extraction. The organic layer was separated, washed with brine, dried (Na2SO4), filtered and evaporated. Trituration of the residue afforded the desired compound after filtration, m.p. 129° C.-30° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11].Cl[C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:20]=2[N:21]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:19]2[O:18][C:17]([NH:1][CH2:2][C@@H:3]3[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]3[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[N:21][C:20]=2[CH:22]=1
Reactant: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CN
Reactant: Clc1ccc2oc(Cl)nc2c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1nc2cc(Cl)ccc2o1
Temperature: 40 °C

Procedure:
A mixture of (2S,3R)-allyl 2-(aminomethyl)-3-methylpiperidine-1-carboxylate (0.804 g, 3.787 mmol), 2,5-dichlorobenzo[d]oxazole (0.712 g, 3.787 mmol) and DIPEA (1 mL, 5.68 mmol) in acetonitrile (15 mL) was heated at 40° C. overnight. The solvent was removed in vacuo and the crude was purified via silica gel with 0˜100% EtOAc/hexanes to obtain the title compound. ESI-MS (m/z): 364 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([O:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Br:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.6 %

Procedure:
To a solution of 2-bromo-4-methylphenol (1.5 g, 8.0 mmol) in N,N-dimethylformamide (40 mL), potassium carbonate (1.32 g, 9.6 mmol) was added and furthermore benzyl bromide (1.05 mL, 8.8 mmol) was added thereto. The mixture solution was stirred at room temperature for 12 hours, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (1.72 g, 77%).
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:13]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:13][C:8]1[CH:9]=[C:10]([O:11][CH3:12])[C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cccc(C(=O)O)c1O
Solvent: CC(=O)O
Product: COc1cc(Cl)cc(C(=O)O)c1O

Procedure:
step a) 2-hydroxy-3-methoxy-benzoic acid (13) is chlorinated for example with N-chlorosuccinimide in acetic acid to yield 5-chloro-2-hydroxy-3-methoxy benzoic acid (14); step b) the methoxy group of compound (14) is reacted with hydrobromic acid in acetic acid to yield 5-chloro-2,3-dihydroxybenzoic acid (15);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]([CH3:17])[C:10]1=[O:18].Cl[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:28])[F:29])=[CH:22][N:21]=2)=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]([CH3:17])[C:10]1=[O:18]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Cn1c(=O)[nH]c(=O)n(-c2cc(O)ccc2Br)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)n(-c2cc(Oc3ncc(C(F)(F)F)cc3Cl)ccc2Br)c1=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(2-bromo-5-hydroxyphenyl)-3-methyl-s-triazine-2,4,6(1H,3H,5H)-trione (5.29 g, 0.0168 mol), 2,3-dichloro-5-trifluoromethylpyridine (5.44 g, 0.025 mol) and potassium carbonate (3.45 g, 0.025 mol) in N,N-dimethylformamide is stirred at 80° C for 18 hours, cooled to room temperature and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. The solid is recrystallized from an ether/hexanes solution to give the title product as a yellow solid, mp 97°-110° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].C([O:9][C@@H:10]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=NC=N[CH:41]=2)=[CH:32][CH:31]=1)[C@H:11]([CH2:15][CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)[C:12]([OH:14])=[O:13])=O.O1C[CH2:45][CH2:44][CH2:43]1>CO>[OH:9][C@@H:10]([CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:45][C:44]([O:4][CH3:1])=[CH:43][CH:37]=2)=[CH:34][CH:35]=1)[C@H:11]([CH2:15][CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)[C:12]([OH:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Reactant: O=CO[C@@H](CCc1ccc(-c2cncnc2)cc1)[C@H](CCn1nnc2ccccc2c1=O)C(=O)O
Agent: [K+]
Solvent: CO
Product: COc1ccc(-c2ccc(CC[C@H](O)[C@H](CCn3nnc4ccccc4c3=O)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (0.151 g) was added to a solution of the compound obtained from step h above (0.5 g) in methanol (5 mL) and tetrahydrofuran (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The solvents were evaporated and the residue was taken into water and ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by preperative thin layer chromatography using 10% methanol in dichloromethane as eluent to afford the title compound (0.008 g).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[O:11]([CH2:19][CH2:20][CH2:21][OH:22])[Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(N(CC)CC)C.Cl>C(Cl)Cl>[O:11]([CH2:19][CH2:20][CH:21]=[O:22])[Si:12]([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCCC=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
DMSO (24 mmol) is added to oxalyl chloride (11 mmol) in 40 mL of CH2Cl2 cooled to −78° C. After 15 minutes, alcohol 46 (10 mmol) is added. After an additional 15 minutes, triethylamine (50 mmol) is added. The mixture is allowed to warm to 0° C. and then poured into 0.1 M HCl (100 mL). The phases are separated, and the aqueous phase is extracted with ethyl acetate (2×100 mL). The organic phases are washed with water (100 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The mixture is purified by flash chromatography to give the product as a colorless oil.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[CH3:19][N:20]1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH:37]([O:40][C:41]1[C:49]([O:50][CH3:51])=[CH:48][CH:47]=[CH:46][C:42]=1[CH2:43]CN)([CH3:39])[CH3:38].CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[CH:37]([O:40][C:41]1[C:49]([O:50][CH3:51])=[CH:48][CH:47]=[CH:46][C:42]=1[CH2:43][N:20]([CH3:19])[C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]1[CH:9]=[N:10][C:11]2[NH:12][C:3](=[O:2])[CH2:4][CH2:5][C:6]=2[CH:7]=1)([CH3:38])[CH3:39]
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: COc1cccc(CCN)c1OC(C)C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: COc1cccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)c1OC(C)C
Yield: 83 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting (2-isopropoxy-3-methoxy-benzyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (326 mg, 83%) was prepared as a white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.6 (s, 1H), 8.36 (d, J=17.3 Hz, 1H), 8.10-7.98 (m, 1H), 7.50 (d, J=15.3 Hz, 1H), 7.28-7.17 (m, 1H), 7.05-6.93 (m, 2H), 6.63 (dd, J=7.3, 7.3 Hz, 1H), 5.77 (br s, 1H), 4.77-4.63 (m, 2H), 4.59-4.45 (m, 1H), 3.79 (s, 3H), 3.08-2.81 (m, 5H), 2.56-2.44 (m, 2H), 1.23 (t, J=5.7 Hz, 6H); MS (ESI) m/e 410 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH2:16][CH3:17].[NH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>CC(O)C>[CH2:14]([C:13]1[N:19]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCC(=O)Nc1cnc2ccccc2c1Cl
Reactant: NOCCCCNC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCCc1nc2cnc3ccccc3c2n1OCCCCNC(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 76.5 %

Procedure:
N-(4-Chloroquinolin-3-yl)valeramide (1.97 g), benzyl (4-aminooxybutyl)carbamate (2.99 g), triethylamine (0.89 g) and 2-propanol (40.69 g) were combined and heated at 80° C. for 3.5 hours. The reaction was cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure. Dichloromethane (20 mL) was added to the resulting solid and the mixture was stirred for twenty minutes. Undissolved solid was removed by filtration and the filtrate was washed with two 10 mL portions of water that had been made slightly acidic by the addition of 20 drops of hydrochloric acid (1.2 M). The organic fraction was dried and concentrated under reduced pressure. The crude solid was recrystallized from tetrahydrofuran to provide 2.56 g of benzyl 4-{[2-butyl-1H-imidazo[4,5-c]quinolin-1-yl]oxy}butylcarbamate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:20])[O:19]CCO2)=[CH:11][C:10]=1[CH2:21][CH2:22][OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:19])[CH3:20])=[CH:11][C:10]=1[CH2:21][CH2:22][O:23][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(c2ccc(OCc3ccccc3)c(CCO)c2)OCCO1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Temperature: 0 °C

Procedure:
2-[2-Benzyloxy-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]ethanol (9.0 g) was dissolved in N,N-dimethylformamide (100 ml), and 60% sodium hydride in oil (1.26 g) was added to the solution under ice-cooling with stirring. After reaction for an hour at room temperature, benzyl bromide (3.75 ml) was added to the reaction mixture under ice-cooling with stirring, followed by reaction for 16 hours at room temperature. Ice (100 g) and water (100 ml) were added to the reaction mixture, and the resulting mixture was extracted with diethyl ether, then the solvent was removed in vacuo. The residue was dissolved in 1,2-dimethoxyethane (50 ml), and 1 N hydrochloric acid (10 ml) was added to the solution, then the resulting mixture was stirred for 30 minutes at room temperature. Water was added to the reaction mixture, and the resulting mixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/diethyl ether=2/1) gave 4'-benzyloxy-3'-(2-benzyloxyethyl)acetophenone (8.5 g) as an oil.
Reaction SMILES: [CH:1](=[C:8]1[CH2:12][N:11]([C:13]([O:15]C(C)(C)C)=O)[C@H:10]([C:20]([OH:22])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH2:32]([N:34]1[C:46]2[CH:45]=[CH:44][C:43]([NH2:47])=[CH:42][C:41]=2[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH3:33]>>[C:13]([N:11]1[CH2:12][C:8](=[CH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]1[C:20]([NH:47][C:43]1[CH:44]=[CH:45][C:46]2[N:34]([CH2:32][CH3:33])[C:35]3[C:40]([C:41]=2[CH:42]=1)=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:22])(=[O:15])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=Cc2ccccc2)C[C@H]1C(=O)O
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=Cc4ccccc4)CN3C(=O)c3ccccc3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, benzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 81% purity by LC/MS. MS(ESI+): m/z=500.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=O)[CH3:11].Cl.[NH2:14][OH:15].N1C=CC=CC=1>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[N:14][OH:15])[CH3:11]
Reactant: CC(=O)Cc1ccc(Cl)cc1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(Cc1ccc(Cl)cc1Cl)=NO
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
A solution of 1-(2,4-dichlorophenyl)-propan-2-one (3.46 g, 16.7 mmole) in methanol (40 ml) was treated with hydroxylamine hydrochloride (1.40 g, 20.6 mmol) followed by pyridine (1.7 ml, 20.6 mmol). The resulting mixture was stirred at ambient temperature over night for 16 hours. The reaction mixture was poured onto water (200 ml). The solid product was collected by filtration, washed with water and dried (40° C., 100 mbar). 3.63 g (100% of theory) of 1-(2,4-dichlorophenyl)-propan-2-one oxime was obtained in form of a white solid (m.p. 120-124° C.).